PROJECT SUMMARY/ABSTRACT Comorbid posttraumatic stress disorder and major depressive disorder (PTSD+MDD) is the most common pathological response to trauma and represents a major public health burden. Unfortunately, knowledge regarding the neurobiological mechanisms underlying this comorbidity is extremely limited. Without such an understanding, treatment outcomes for this common constellation will remain poor. This K23 Career Development Award aims to provide the PI with the necessary training to become an independent investigator conducting programmatic research delineating the mechanisms underlying PTSD+MDD. Toward this end, the candidate proposes the following training objectives: (1) to acquire expertise in the assessment of executive dysfunction, (2) to gain the requisite knowledge and skills in neuroimaging to conduct independent research of a neurobiologically-based model of PTSD+MDD, and (3) to obtain advanced training in statistical methods. An expert team of mentors has been assembled to support these training goals. The overall research objective of the proposed project is to use an experimental medicine conceptualization of repeated ketamine infusions as a probe to (1) characterize neurobiological factors underpinning PTSD+MDD, (2) demonstrate that modulation of corticolimbic functional connectivity generates clinical improvement and (3) validate a coherent model of PTSD+MDD to inform future research, treatment, and conceptualizations. The central hypothesis is that corticolimbic dysconnectivity is associated with clinical symptoms, rumination and cognitive dysfunction in PTSD+MDD and that ketamine infusions correct dysconnectivity thereby improving clinical symptoms, rumination, and cognition. The specific aims of this research are (1) to examine how baseline PTSD+MDD clinical presentation, cognitive function and neurocircuitry predicts clinical response to ketamine infusions, (2) to examine the association of changes in corticolimbic circuitry with changes in clinical symptoms and cognition following either ketamine or saline infusions, and (3) to examine cognition, rumination, and neurocircuitry in a larger cohort of trauma exposed subjects and healthy controls. Innovative aspects of this project include: (1) Method: Use of ketamine as an experimental medicine probe to characterize biological substrates underlying a coherent model of PTSD+MDD; (2) Design: Application of pre- and post-treatment neuroimaging assessments to identify biomarkers predicting response to an empirically validated treatment for PTSD+MDD; (3) Concept: Proposing a novel model of PTSD+MDD that is built on neuroanatomical and cognitive functioning systems implicated in the pathophysiology of PTSD+MDD. The proposed research is significant because it proposes a coherent model of PTSD+MDD that has the potential to advance our understanding of individuals with pathological responses to trauma.